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首页> 外文期刊>International Journal of Molecular Epidemiology and Genetics >Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells significantly increases 4-hydroxytamoxifen-induced apoptosis
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Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells significantly increases 4-hydroxytamoxifen-induced apoptosis

机译：乳腺癌细胞中磺基转移酶同工型1A1（SULT1A1）的表达显着增加4-羟他莫昔芬诱导的细胞凋亡

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摘要

Previously, we reported a strong association of the high activity SULT1A1*1 allele and overall survival of patients receiving tamoxifen therapy, indicating that sulfation of 4-hydroxytamoxifen (4-OHT) via SULT1A1 may contribute to the therapeutic efficacy of tamoxifen treatment. In most, but not all cases, sulfation is considered to be an elimination pathway; therefore we sought to define the biological mechanism by which increased sulfation of tamoxifen could provide a therapeutic benefit. We compared the antiproliferative and apoptotic responses between MCF7-SULT1A1 expressing cells and control MCF7 pcDNA3 cells when treated with 4-OHT. We observed a greater than 30% decrease in cell proliferation in MCF7-SULT1A1 expressing cells at physiological concentrations of 4-OHT, and significant cell death in SULT1A1-expressing cells treated with 2µM 4-OHT for 48 hours compared to control cells (p<0.05). Within 24 hours of drug treatment, an 80% increase in apoptosis in SULT1A1-expressing cells was apparent when compared to similarly treated cells that did not express SULT1A1. We also observed an increase in endonuclease G, the primary endonuclease expressed in ER-dependent breast cancer cells, which participates in caspaseindependent apoptosis. These data confirm that SULT1A1-mediated biotransformation of 4-OHT is important in the efficacy of 4-OHT cytotoxicity in breast tumors, and reveals a potential role for sulfated metabolites in the efficacy of tamoxifen therapy.
机译：以前，我们报道了高活性SULT1A1 * 1等位基因与接受他莫昔芬治疗的患者的整体生存率密切相关，这表明通过SULT1A1进行4-羟基他莫昔芬（4-OHT）的硫酸化可能有助于他莫昔芬的治疗功效。在大多数（但不是全部）情况下，硫酸盐被认为是消除途径。因此，我们试图确定增加他莫昔芬硫酸盐提供治疗益处的生物学机制。我们比较了用4-OHT处理MCF7-SULT1A1表达细胞与对照MCF7 pcDNA3细胞之间的抗增殖和凋亡反应。我们观察到，在生理浓度为4-OHT的MCF7-SULT1A1表达细胞中，细胞增殖下降幅度超过30％，与对照组相比，用2µM 4-OHT处理48小时的SULT1A1表达细胞中细胞明显死亡（ 0.05）。与不表达SULT1A1的类似处理的细胞相比，在药物治疗的24小时内，表达SULT1A1的细胞的凋亡明显增加了80％。我们还观察到内切酶G的增加，内切酶G是在ER依赖性乳腺癌细胞中表达的主要内切核酸酶，参与了caspase依赖性细胞凋亡。这些数据证实，SULT1A1介导的4-OHT生物转化在乳腺癌中对4-OHT细胞毒性的功效中很重要，并且揭示了硫酸代谢产物在他莫昔芬疗法中的潜在作用。

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